Preventives and/or remedies for hyperphosphatemia

ABSTRACT

Provided in a phosphate ion adsorbent containing a weakly basic anion exchange resin as an active ingredient which aims at providing preventives and/or remedies for hyperphosphatemia having a high selectivity for the adsorption of phosphate ion and showing an effect of lowering blood phosphorus level and another effect of suppressing phosphorus excretion into the urine.

TECHNICAL FIELD OF THE INVENTION

[0001] The invention relates to a phosphate ion adsorbent and apreventive and/or a remedy for hyperphosphatemia.

BACKGROUND ART

[0002] In patients of renal function disorder, disorder of phosphorusexcretion in the urine is observed, and in the early stages of renalfailure a renal compensation mechanism works to keep phosphorushomeostasis, temporarily showing increase of phosphorus excretion byinhibiting a phosphorus re-absorption due to increase of PTH(parathyroid hormone). However, it becomes impossible to keep thehomeostasis due to aggravation of a renal lesion and lowering of a renalfunction. As a result, hyperphosphatemia due to reduction of phosphorusexcretion and a remarkable increase of PTH occurs. The accumulatedphosphorus induces, as direct actions, lowering of blood calcium,acceleration of PTH production/secretion, ectopic calcification andrenal osteodystrophy due to suppression of vitamin D activation. Also,as indirect actions via high PTH level, central and peripheral nervedisorders, myocardial disorders, hyperlipemia, saccharometabolismdisorders, muscle disorders, growth retardation, cardiac conductiondisorders, alveolar diffusion disorders, arteriosclerosis andimmunodeficiency are shown. Further, as to phosphorus the aspect as auremic substance and its direct or indirect involvement forcomplications of renal failure are known (Jin to Toseki, 37, 2: 321,1994).

[0003] Even if treatment is changed to a dialysis therapy due to renalfailure, the above disease conditions and complications continue unlessthe phosphorus homeostasis is maintained. Consequently, treatment ofhyperphosphatemia is essential for dialysis patients of renal failure orpatients before dialysis. At present, in the treatment ofhyperphosphatemia a diet therapy or an oral phosphorus adsorbent areused. In the diet therapy low protein diet is used, though the intakefor long period is difficult, and protein intake of a certain degree isunavoidable, wherefore the effect to lower phosphorus in blood cannotnecessarily be expected.

[0004] As oral phosphorus adsorbents, mainly three types in thefollowing are currently used.

[0005] 1) Aluminum preparation (aluminum hydroxide)

[0006] 2) Calcium preparation (calcium carbonate, calcium acetate)

[0007] 3) Magnesium preparation (magnesium carbonate)

[0008] In 1) side effects of aluminum encephlopathy and aluminumosteopathy due to aluminum absorption are problems; in 2) theadsorbability is inferior compared with the aluminum preparation, andadditionally the dose is also high, giving a problem of inducinghypercalcemia due to calcium absorption; further, in 3) there is aproblem of inducing hypermagnesemia as in the calcium preparation.

[0009] Methods for using an anion exchange resin as an oral phosphorusadsorbent have been reported in recent years. In JP, A, 9-504782(WO95/05184) an anion exchange resin in which polyallyl amine iscrosslinked with epichlorohydrin is reported as a phosphoric acidadsorbent. Also, in JP, A, 8-506846, WO96/25440, it is reported that theanion exchange resin having a guanythidyl group selectively adsorbsphosphoric acid. Further, in JP, A, 9-295941,2-methylimidazole-epichlorohydrin copolymer and cholestyramine which arebile acid adsorbents are applied as oral phosphorus adsorbents. However,all have a defect that use of a high dose is necessary because of aremarkable reduction of phosphate absorption.

[0010] As described above, in a currently carried out hyperphosphatemiatreatment, bad effects are concerned in any method. Therefore, thepresent situation is such that a better remedy for hyperphosphatemia hasnot been found out up to now.

[0011] On the other hand, although it is known that a weakly basic anionexchange resin known under the trade name, for example, such as IonacA-365 (Sybron Chemicals Co.) is used to remove hydrochloric acid in anaqueous system and a non-aqueous system, there has been no report todate in which this is used as a phosphoric acid adsorbent.

DISCLOSURE OF THE INVENTION

[0012] The invention is accomplished in view of the problems of theabove prior art, and is to provide a preventive and/or a remedy forhyperphosphatemia having a high selectivity toward a phosphate ionadsorption action, further having a lowering action of blood phosphorusconcentration and a lowering action of urinary phosphorus excretion.

[0013] The inventors made extensive researches to solve the aboveproblems and found out that a weakly basic anion exchange resin , whichwas only used as main uses for removal of hydrochloric acid in anaqueous system and a non-aqueous system, surprisingly has a phosphoricacid adsorption action, a lowering action of blood phosphoric acidconcentration and a lowering action of urinary phosphorus excretion, andaccomplished the invention.

[0014] Namely, the invention relates to a phosphate ion adsorbentcomprising as an active ingredient a weakly basic anion exchange resin.

[0015] Also, the invention relates to the above phosphate ion adsorbent,characterized in that the weakly basic anion exchange resin is acopolymer containing as monomer components an acrylic acid type compoundhaving a tertiary amino group and divinylbenzene.

[0016] Further, the invention relates to the above phosphate ionadsorbent, characterized in that the copolymer further contains asmonomer components one or more components selected from the groupconsisting of acrylonitrile, vinylimidazole, vinylhistidine,vinylpyrazine and diaminodiphenylmethane.

[0017] The invention also relates to the above phosphate ion adsorbent,characterized in that the weakly basic anion exchange resin has porousbead structure.

[0018] Also, the invention relates to the above phosphate ion adsorbent,characterized in that the weakly basic anion exchange resin is IonacA-365 (trade name; Sybron Chemicals Co.).

[0019] Further, the invention also relates to a preventive and/or aremedy for hyperphosphatemia, characterized in that it contains theabove phosphate ion adsorbent.

[0020] A phosphate ion adsorbent and a preventive and/or a remedy forhyperphosphatemia according to the invention not only can overcome badeffects shown in usual weakly basic anion exchange resins and thealuminum, calcium and magnesium preparations that have been used as apreventive and/or a remedy for hyperphosphatemia, but also have anextremely high selectivity toward a phosphorus adsorption actioncompared with oral phosphorus adsorbents reported so far in which anionexchange resins are used.

[0021] As described above, considering that in general, a weakly basicanion exchange resin is a resin that has been used up to now at theindustrial level for the purpose of decoloring, demineralization orhazardous substance removal for solvent, a supplied water or a wastewater, the effect attained by the invention is totally surprising.

[0022] Weakly basic anion exchange resins used in the inventiontypically have as its main backbone copolymers of an acrylic acid typecompound, which have a tertiary amino group, for example, such asacrylamide or acrylate, and divinylbenzene, and further may contain asother monomer components acrylonitrile, vinylimidazole, vinylhistidine,vinylpyrazine, diaminodiphenylmethane or the like further in a rangethat it is pharmaceutically acceptable and does not reduce the effect.Preferably they are weakly basic polyacrylate type resins having porousbead structure.

[0023] Although preparation of a weakly basic anion exchange resin usedin the invention can be carried out by a conventional method known bypublications, etc., specifically it can be carried out bycopolymerization of a monovinyl monomer such as acrylic acid or itsalkyl ester and divinylbenzene and reaction of this copolymer withpolyalkylene polyamine. Additionally, this copolymer can becopolymerized with other monomers such as acrylonitrile, vinylimidazole,vinylhistidine, vinylpyrazine or diaminodiphenylmethane in a range thatit is pharmaceutically acceptable and does not lose the effect.

[0024] Illustrative of such a weakly basic anion exchange resin is, forexample, Ionac A-365 (trade name; Sybron Chemicals Co.) which is beingmarketed with the main use for removal of, hydrochloric acid in anaqueous system and a non-aqueous system.

[0025] The phosphoric acid adsorbent and the preventive and/or theremedy for hyperphosphatemia according to the invention lower bloodphosphorus concentration and urinary phosphorus excretion. Therefore,the preventive and/or the remedy for hyperphosphatemia according to theinvention are expected to have a preventive and/or therapeutic effecttoward a renal function disorder, chronic renal failure, dialysis,hypocalcemia, excess secretion of parathyroid hormone (PTH), suppressionof vitamin D activation , ectopic calcification or the like whereinhyperphosphatemia is considered to be the cause of disease. Further, thepreventive and/or remedy for hyperphosphatemia of the invention areexpected to exert a remarkable preventive effect and/or therapeuticeffect toward PTH increase due to hyperphosphatemia, secondaryhyperparathyroidism via vitamin D lowering, renal osteodystrophy,uremia, central and peripheral nerve disorders, anemia, myocardialdisorders, hyperlipemia, saccharometabolism disorders, itch, dermalischemic ulcer, tendon rupture, reproductive dysfunction, muscledisorder, growth retardation, cardiac conduction disorders, alveolardiffusion disorders, arteriosclerosis, immunodeficiency, etc.

BRIEF DESCRIPTION OF DRAWINGS

[0026]FIG. 1 is a figure which shows the bound amounts with phosphoricacid of the weakly basic anion exchange resin (Ionac A-365; SybronChemicals Co.) and that of calcium carbonate with phosphoric acid inExample 1.

[0027]FIG. 2 is a figure which shows the increased amounts of urinaryphosphorus excretion calculated from the difference between before andafter the drug administration in Example 2; in the figure * and ** showsignificant differences compared with control (p<0.05 and p<0.01respectively, student-t test). Further, in the figure # shows asignificant difference compared with the calcium carbonateadministration group ((p<0.05, student-t test).

[0028]FIG. 3 is a figure which shows the blood phosphorus concentrationsafter the drug administration in Example 3, and in the figure * shows asignificant difference compared with control (p<0.05, student-t test).

[0029]FIG. 4 is a figure which shows the amounts of urinary proteinexcretion before and after the drug administration in Example 3, and inthe figure * and ** show significant differences compared with control(p<0.05 and p<0.01 respectively, student-t test).

[0030]FIG. 5 is a figure which shows the adsorption amounts ofphosphoric acid toward Ionac A-365 and Renagel in Example 4.

[0031]FIG. 6 is a figure which shows the adsorption amounts of bile acidtoward Ionac A-365 and Renagel in the example 4.

MODE FOR CARRYING OUT THE INVENTION

[0032] In the following described is an embodiment on a phosphate ionadsorbent which uses the above weakly basic anion exchange resin and apreventive and/or a remedy for hyperphosphatemia of the invention.

[0033] As a phosphate ion adsorbent and a preventive and/or a remedy forhyperphosphatemia of the invention, although the above ion exchangeresin itself can be used as an active ingredient, since this has aparticle size of 0.3-1.2 mm, preferably vacuum drying is appllied atroom temperature, further being followed by a step of removingimpurities with a sieve after pulverization to produce a pharmaceuticalcomposition using an ordinarily used additive for a pharmaceuticalpreparation. Illustrative of dosage forms of such a pharmaceuticalcomposition are tablets, capsules, fine granules, pills, troches,liquids or the like, and these are administered orally.

[0034] An oral pharmaceutical composition can be prepared by ordinarilyused conventional methods such as mixing, filling and compressing.Further, by use of a repetitive blend procedure an effective ingredientcan be distributed using a large amount of filler in a pharmaceuticalcomposition. For example, tablets or capsules used for oraladministration are favorably administered as a dosage unit form, whichmay contain conventionally used carriers for preparations such asbinders, fillers, diluents, compressing agents, lubricants,disintegrators, colorants, flavoring agents and wetting agents. Tabletscan be made as coated tablets using, for example, a coating agentaccording to widely known methods.

[0035] Illustrative of preferable fillers are cellulose, mannitol,lactose, etc., and disintegrators such as starch, polyvinylprrolidoneand a starch derivative such as sodium starch glycolate or lubricantssuch as sodium laurylsulfate can be used as additives for preparations.A pharmaceutical composition of an oral liquid form is provided as, forexample, aqueous or oil suspensions, solutions, emulsions, syrups orelixirs, or as a dry pharmaceutical composition which can be redissolvedbefore use by water or an appropriate medium.

[0036] In such liquids can be blended conventional additives, forexample, such as precipitation preventing agents including sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose,carboxymethylcellulose, aluminum stearate gel or hydrogenated ediblefat; emulsifiers such as lecithin, sorbitan monooleate or gum arabic;oily esters such as almond oil, finely distilled coconut oil or glycerinester; non-aqueous solvents such as propylene glycol or ethyl alcohol(edible oil can also be contained); preservatives such as methyl esterof p-hydroxybenzoic acid or sorbic acid, and conventional flavoringagents or colorants if needed.

[0037] In the case of the above oral pharmaceutical compositions, forexample, such as tablets, capsules or fine granules, usually contain5-95 wt. %, preferably 25-90 wt. % of the effective ingredient. Theremedy of the invention is useful for prevention and/or treatment ofhyperphosphatemia caused by diseases of a renal function disorder andamong them, is particularly useful for prevention and/or treatment ofhyperphosphatemia accompanied by renal function disorders. The doses ofthe preventive and/or the remedy for hyperphosphatemia of the inventionmay appropriately be determined according to the age, health condition,body weight and disease severity of the patient, the kind and frequencyof therapy and treatment simultaneously carried out, the nature of thedesired effect, and the like. Generally, the daily dose for an adult maybe 1-60 g in the active ingredient amount and may be administered onceor several times a day.

[0038] In the following, the invention is explained concretely by theexamples. However, the invention is not limited thereto. Here, IonacA-365 (trade name; Sybron Chemicals Co.) pulverized and dried forpurification as the weakly basic anion exchange resin and calciumcarbonate described in Japanese Pharmacopeia were used.

[0039] Further, Renagel (Renagel®; manufactured by Geltex Co., U.S.) wasused as a comparative drug.

EXAMPLE 1 Adsorption Test of Phosphoric Acid at the Ion Concentration ofIntestinal Juice

[0040] Considering the ion concentration of intestinal juice, the weaklybasic anion exchange resin (Ionac A-365; Sybron Chemicals Co.) orcalcium carbonate was added to an aqueous solution in which NaH₂PO₄ 5 mMwas dissolved in such a way that each became 1 mg/ml, adjusted to pH 6.8by sodium hydroxide, and stirred at 37° C. for 1 hour. Then, the resinwas removed by a filter, and phosphoric acid which was not bound to theresin was measured by an inorganic phosphrus measurement reagent (P TestWako), whereby the amount of phosphoric acid bound to the resin wascalculated based on its value. the results are shown in FIG. 1. IonacA-365 showed a higher binding amount with phosphoric acid compared withcalcium carbonate.

EXAMPLE 2 Effects on Amount of Blood and Urinary Phosphorus in NormalRats

[0041] Using male SD rats (aged 8 weeks), the experiments on suppressiveeffects for the increase of urinary phosphorus amount in the weaklybasic anion exchange resin (Ionac A-365; Sybron Chemicals Co.) orcalcium carbonate were carried out as follows.

[0042] Namely, after the rats were given with feed (20 g/rat/day)containing 0.3% phosphorus for 7 days, feed (20 g/rat/day) containing0.58% phosphorus was mixed with 0.5 g of Ionac A-365 or calciumcarbonate and the mix feed was further administered to the rats for 5days. Further, urine was collected for 24 hours before the drugadministration and 5 days after the drug administration, and the amountof urinary phosphorus was calculated based on the urinary phosphorusconcentration and the amount of urine. The urinary phosphorusconcentration was measured by an inorganic phosphorus measurementreagent (P Test Wako). The increased amount of urinary phosphorusexcretion was calculated based on the obtained difference of urinaryphosphorus amount between before drug administration and 5 days afterthe drug administration, and compared with that of thenon-administration group (control). As for rats in each group, 6 rats ineach were subjected to the experiments. The obtained results are shownin FIG. 2. The increase of urinary phosphorus excretion in the calciumcarbonate administration was significantly suppressed compared with thatof control. Also, although the increase of urinary phosphorus excretionwas significantly suppressed in the Ionac A-365 administration group,the effect was larger than that of the calcium carbonate administrationgroup.

EXAMPLE 3 Effects on Blood Phosphorus Concentration and Renal Functionin Rats with ⅚ Nephrectomy

[0043] Using male SD rats (aged 9 weeks), the experiments on the effectsfor the lowering action of urinary phosphorus amount and the renalfunction in the weakly basic anion exchange resin (Ionac A-365; SybronChemicals. Co.) or calcium carbonate were carried out as follows.

[0044] Namely, ⅔ of the left kidney was removed, after 1 week the rightkidney being totally removed to make rats with ⅚ nephrectomy. After 1week, a mixed feed administration of calcium carbonate or Ionac A-365started. As a powder feed for rat MF manufactured by Oriental Yeast wasused, and the administration dose was made 0.3 g content in 15 g of thefeed. 12 weeks after the preparation of rats with ⅚ nephrectomy, bloodwas collected from the caudal vein, and the blood phosphorusconcentration was measured by an inorganic phosphorus measurementreagent (P Test Wako). Also, urine was collected for 24 hours before thenephrectomy and 12 weeks after the nephrectomy, and the urinary proteinconcentration being measured by a protein measurement reagent (ProteinAssay Kit, Bio-lad). As for rats in each group, 9 rats in each weresubjected to the experiments. The obtained results are shown in FIG. 3and FIG. 4. As shown in FIG. 3, in the calcium carbonate administrationgroup there was no significant difference in blood phosphorusconcentration compared with control. In the Ionac A-365 administrationgroup a significant lowering of blood phosphorus concentration wasobserved. Also, as shown in FIG. 4, although in control the amount ofurinary protein excretion increased remarkably at 12 weeks afterpreparation of rats with ⅚ nephrectomy and deterioration of kidneyfunction was shown, in the calcium carbonate administration group, theincrease of urinary protein excretion amount was significantlysuppressed compared with control. Also, in the Ionac A-365administration group the increase of urinary protein excretion amountwas significantly suppressed, its action intensity being larger thanthat of the calcium carbonate administration group, showing thesuppressive effect against deterioration of kidney function.

EXAMPLE 4 Effects of High Concentration Bile Acid on Phosphoric AcidAdsorption Specificity

[0045] With an aim to investigate the effects of a high concentrationbile acid on a phosphoric acid adsorption specificity, the adsorptionproperty of an anion exchange resin for phosphate ion and glycolic acidwas examined. Considering the ion concentration in intestinal juiceprepared were one preparation having been added with Ionac A-365 1 mg/mlto an aqueous solution in which NaH₂PO₄ 5 mM and glycolic acid 20 mM wasdissolved and another preparation having been added with Renagel 1 mg/mlto an aqueous solution in which NaH₂PO₄ 5 mM and glycolic acid 20 mM wasdissolved. Each was adjusted to pH 6.8 by sodium hydroxide, and stirredat 37° C. for 1 hour. Then, the resin was removed by an ultrafiltermembrane, and the amount of phosphoric acid which was not adsorbed tothe resin was measured by an inorganic phosphorus measurement reagent(registered trade mark, P Test Wako; manufactured by Wako Junyaku KogyoCo.), whereby the amount of phosphoric acid adsorbed and removed by eachanion exchange resin was calculated based on this measurement value.Further, the amount of glycolic acid not adsorbed to the resin wasmeasured by a bile acid measurement reagent (registered trade mark,Total Bile Acid Test Wako; manufactured by Wako Junyaku Kogyo Co.),whereby the amount of glycolic acid adsorbed and removed by each anionexchange resin was calculated based on this measurement value. Theresults are shown in FIG. 5 and FIG. 6. In the presence of bile acid 20mM Renagel, a control drug (comparative drug), showed a high bile acidadsorption activity. In contrast to this, Ionac A-365 maintained a highphosphoric acid adsorption activity even in the presence of bile acid 20mM, wherein very little the bile acid adsorption was observed.

[0046] Industrial Applicability

[0047] It is found out that a weakly basic anion exchange resin whichhas been used up to now at the industrial level for the purpose ofdecoloring, demineralization or hazardous substance removal of solvent,a supplied water or a waste water is useful as a phosphate ionadsorbent. Since this remarkably suppresses blood phosphorusconcentration and urinary phosphorus excretion, achieving suppressionfor deterioration of kidney function, it is effective for preventionand/or treatment of hyperphosphatemia and useful as a drug.

1. A phosphate ion adsorbent comprising as an active ingredient a weaklybasic anion exchange resin.
 2. The phosphate ion adsorbent according toclaim 1, characterized in that the weakly basic anion exchange resin isa copolymer containing as monomer components an acrylic acid typecompound having a tertiary amino group and divinylbenzene.
 3. Thephosphate ion adsorbent according to claim 2, characterized in that thecopolymer further contains as monomer components one or more componentsselected from the group consisting of acrylonitrile, vinylimidazole,vinylhistidine, vinylpyrazine and diaminodiphenylmethane.
 4. Thephosphate ion adsorbent according to any one of claims 1-3,characterized in that the weakly basic anion exchange resin has porousbead structure.
 5. The phosphate ion adsorbent according to claim 4,characterized in that the weakly basic anion exchange resin is IonacA-365 (trade name; Sybron Chemicals Co.).
 6. A preventive and/or aremedy for hyperphosphatemia, characterized in that it contains thephosphate ion adsorbent according to any one of claims 1-5.